Enzyme inhibitors for metabolic redirection

Abstract

A method is described for improving the pharmacokinetics of a drug in a subject, by co-administering oligomers, preferably PMO's (phosphorodiamidate morpholino oligonucleotides), antisense to RNAs encoding drug-metabolizing enzymes, particularly p450 enzymes. The oligomers reduce production of the drug-metabolizing enzymes, which extends drug half-life and effectiveness and/or decreases drug toxicity.

It is claimed:  
     
       1. A method of inhibiting metabolism of a drug administered to a subject, comprising 
       co-administering with said drug a morpholino antisense oligomer effective to reduce expression of a cytochrome p450 enzyme that catalyzes metabolism of the drug in said subject, by hybridizing to a target RNA molecule which encodes said enzyme,  
       wherein the cytochrome p450 enzyme is selected from the group consisting of CYP2B1, CYP2E1, CYP3A2, and CYP3A4,  
       and wherein said morpholino antisense oligomer has a base sequence selected from the group consisting of: SEQ ID NO: 16, for inhibition of CYP2B1; SEQ ID NOs: 18-20 and 23, for inhibition of CYP2E1; SEQ ID NOs: 24 and 25, for inhibition of CYP3A2; and SEQ ID NOs: 35, 46, and 47, for inhibition of CYP3A4; and is administered transdermally to the subject.  
     
     
       2. The method of  claim 1 , wherein the drug either induces said drug-metabolizing cytochrome p450 enzyme, or is administered to a subject who has been exposed to a xenobiotic agent which induces such an enzyme. 
     
     
       3. The method of  claim 2 , wherein said dnig induces at least one cytochrome p450. 
     
     
       4. The method of  claim 2 , wherein said xenobiotic agent induces at least one cytochrome p450. 
     
     
       5. The method of  claim 1 , wherein the antisense oligomer is at least 15 nucleotides in length. 
     
     
       6. The method of  claim 1 , wherein the antisense oligomer has an uncharged backbone comprising phosphoramidate or phosphorodiamidate linkages. 
     
     
       7. The method of  claim 1 , wherein the antisense oligomer hybridizes to a region of said target RNA with a T m  greater than 37° C. 
     
     
       8. The method of  claim 1 , wherein said cytochrome p450 is CYP3A4. 
     
     
       9. The method of  claim 8 , wherein said subject is a human subject. 
     
     
       10. The method of  claim 3 , wherein said cytochrome p450 is from the CYP3A subfamily, and said drug is phenobarbital or hexobarbital. 
     
     
       11. The method of  claim 3 , wherein said cytochrome p450 is CYP3A4, and said drug is an antibiotic selected from the group consisting of clarithromycin, erythromycin, rifampicin, rifampin, rifabutin, and rapamycin. 
     
     
       12. The method of  claim 3 , wherein said cytochrome p450 is CYP3A4, and said drug contains an estrogen or estradiol. 
     
     
       13. The method of  claim 4 , wherein said cytochrome p450 is CYP3A4, said drug is a protease inhibitor or non-nucleoside reverse transcriptase inhibitor, and said xenobiotic is a CYP3A4-inducing non-nucleoside reverse transcriptase inhibitor. 
     
     
       14. The method of  claim 1 , wherein said oligomer has the sequence presented herein as SEQ ID NO: 47. 
     
     
       15. The method of  claim 8 , wherein said drug is paclitaxel.